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An endogenous molecular clockwork drives various cellular pathways including metabolism and the cell cycle. Its dysregulation is able to prompt pathological phenotypes including cancer. Besides dramatic metabolic alterations, cancer cells display severe changes in the clock phenotype with likely consequences in tumor progression and treatment response. In this study, we use a comprehensive systems-driven approach to investigate the effect of clock disruption on metabolic pathways and its impact on drug response in a cellular model of colon cancer progression. We identified distinctive time-related transcriptomic and metabolic features of a primary tumor and its metastatic counterpart. A mapping of the expression data to a comprehensive genome-scale reconstruction of human metabolism allowed for the in-depth functional characterization of 24 h-oscillating transcripts and pointed to a clock-driven metabolic reprogramming in tumorigenesis. In particular, we identified a set of five clock-regulated glycolysis genes, ALDH3A2, ALDOC, HKDC1, PCK2, and PDHB with differential temporal expression patterns. These findings were validated in organoids and in primary fibroblasts isolated from normal colon and colon adenocarcinoma from the same patient. We further identified a reciprocal connection of HKDC1 to the clock in the primary tumor, which is lost in the metastatic cells. Interestingly, a disruption of the core-clock gene BMAL1 impacts on HKDC1 and leads to a time-dependent rewiring of metabolism, namely an increase in glycolytic activity, as well as changes in treatment response. This work provides novel evidence regarding the complex interplay between the circadian clock and metabolic alterations in carcinogenesis and identifies new connections between both systems with pivotal roles in cancer progression and response to therapy.
Pubmed ID: 30005951 RIS Download
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A supplier of various biochemical products for research in pharmacy and biotechnology as well as the specialty ingredients market. Examples of products include active pharmaceutical ingredients, stem cell therapies, drinking water sanitizers and agriculture services and products.
View all literature mentionsAn integrative interaction database that integrates different types of functional interactions from heterogeneous interaction data resources. Physical protein interactions, metabolic and signaling reactions and gene regulatory interactions are integrated in a seamless functional association network that simultaneously describes multiple functional aspects of genes, proteins, complexes, metabolites, etc. With human, yeast and mouse complex functional interactions, it currently constitutes the most comprehensive publicly available interaction repository for these species. Different ways of utilizing these integrated interaction data, in particular with tools for visualization, analysis and interpretation of high-throughput expression data in the light of functional interactions and biological pathways is offered.
View all literature mentionsInternational functional genomics data collection generated from microarray or next-generation sequencing (NGS) platforms. Repository of functional genomics data supporting publications. Provides genes expression data for reuse to the research community where they can be queried and downloaded. Integrated with the Gene Expression Atlas and the sequence databases at the European Bioinformatics Institute. Contains a subset of curated and re-annotated Archive data which can be queried for individual gene expression under different biological conditions across experiments. Data collected to MIAME and MINSEQE standards. Data are submitted by users or are imported directly from the NCBI Gene Expression Omnibus.
View all literature mentionsCommercial vendor and service provider of laboratory reagents and antibodies. Supplier of scientific instrumentation, reagents and consumables, and software services.
View all literature mentionsCell line SW480 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsThis polyclonal targets Human Soluble VEGF Receptor-1 (Soluble) (sFlt-1, sVEGFR-1)
View all literature mentionsCell line Hep-G2 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line HEK293T is a Transformed cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line SW620 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line HEK293T is a Transformed cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line SW620 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsThis polyclonal targets Human Soluble VEGF Receptor-1 (Soluble) (sFlt-1, sVEGFR-1)
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